PROJECT SUMMARY Background: There is growing concern about the recreational use of synthetic psychoactive cannabinoids (SPCs) sold as `Spice'. Unlike, delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of herbal cannabis, which is a weak efficacy, low affinity, partial agonist of brain cannabinoid receptors (CB1Rs), SPCs are high efficacy, high affinity, full CB1R agonists. Consistent with this profile, while SPCs produce some effects similar to cannabis, they are generally more potent and unpredictable; in fact SPCs have been associated with catastrophic medical and psychiatric adverse outcomes. Despite concerns about the negative consequences of recreational Spice use, there is very little controlled data on the effects of acute or repeated exposure to SPCs on the brain endocannabinoid system or brain function in general. The main purpose of the proposed study, is to compare CB1R availability in Spice dependent (Spice users [SUs]), cannabis dependent (cannabis users [CUs]) and healthy controls (HCs). Furthermore, cognitive test performance will be assessed in order to relate the receptor availability to domains germane to ?real world? functioning. Given the plethora of Spice products and their constituent SPCs, differences in their pharmacology, and the limited scope of an R21 application, we will need to limit the study to the most prevalent SPC around the time around the time the study is expected to be initiated. The latter will identified based on information gleaned from the National Forensic Laboratory Information System (NFLIS), local DEA office, local emergency rooms, news media, Poison Control Centers and blogs about Spice use (e.g., Drugs-Forum). Cognitive test performance will be assessed in order to relate receptor availability to ?real world? functioning. Similarly, cannabinoid-sensitive electrophysiological measures of information processing (P300 and gamma driving) will relate receptor availability to proximal biomarkers of brain function. Primary Hypothesis: Spice users will show lower CB1R availability compared to CUs and HCs. Exploratory Hypotheses: Compared to CUs and HCs, SUs will show worse cognitive test performance, and cannabinoid-sensitive electrophysiological indices of information processing (P300 amplitude and gamma oscillations). Methods: Using the CB1R specific PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT), CB1R availability will be measured in SUs, CUs and HCs. Cognitive function will be assessed using the CANTAB battery. P300 and gamma oscillations will also be measured. Preliminary Results: Spice Users (n=2) show robust reductions in CB1R availability relative to cannabis users (n=11) and healthy controls (n=19). The magnitude of the differences (effects size d) between SUs vs. CUs, and HCs were -1.29 and -6, respectively. Differences between SUs and CUs were comparable in magnitude to the differences between CUs and HCs (~15%, d=1.19).